Patients with lipodystrophies are predisposed to insulin resistance and its metabolic complications including diabetes mellitus, dyslipidemia and hepatic steatosis. Treatment of these conditions poses a significant challenge as available conventional therapies are not very effective. Recent clinical trials of human recombinant leptin in severely hypoleptinemic patients with lipodystrophies have shown promising results but whether leptin will be equally efficacious in those with mild hypoleptinemia is unclear. Therefore, we propose to investigate novel therapeutic approaches such as extremely low fat diets, leptin, cholic acid and pioglitazone (a PPAR gamma agonist) for patients with lipodystrophies. The project has the following aims: 1) to compare the acceptability and metabolic effects of extremely low fat (<10% of total energy) and moderate fat (35% of total energy) diets, 2) compare the efficacy and safety of leptin therapy in mildly or severely hypoleptinemic patients with familial partial lipodystrophies, 3) to evaluate the efficacy and safety of cholic acid therapy in treating hepatic steatosis and 4) to evaluate the safety and metabolic effects of pioglitaznoe. To accomplish these aims, we will enroll ~ 72 patients with various types of generalized and partial lipodystrophies (excluding HIV-infected patients) with metabolic complications in randomized, crossover (aims 1,3 and 4) and randomized, parallel design studies(aim 2). We will study body fat distribution by anthropometry, dual energy X-ray absorptiometry and magnetic resonance imaging, will measure hepatic triglyceride concentration using 1-H magnetic resonance spectroscopy, insulin sensitivity by euglycemic, hyperinsulinemic clamp technique and also measure plasma lipoproteins, glucose, hemoglobin A1c and insulin. Our results may help in designing therapeutic approaches to metabolic complications in patients with lipodystrophies. Additionally, the findings may be applicable to treating metabolic complications in patients with obesity and type 2 diabetes.